The Language of Life How Cells Communicate in Health and Disease (2005) / Chapter Skim
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6 The Virtual Cell
Pages 241-260

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From page 241...
... Gilman, the Alliance's creator, director, taskmaster, and muse. Regal in his formal dark suit and crisp white shirt, Gilman looks the part of the elder statesman as he greets his guests.
From page 242...
... "Sequencing the genome is enabling us to think about bigger questions in unbiased, nonhypothetical ways," Gilman noted in an interview at the time of the launch. But solutions to bigger questions, he believes, are more likely to come from the collaborative efforts of many scientists, pooling resources, sharing data, and developing the analytic tools to manage and mine those data than from the time-honored style of research based on individual scientists working by themselves, for themselves -- solutions, Gilman argues, that can be facilitated by modern communications technologies like the Internet.
From page 243...
... The balance will be made up by funds from the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, paid subscriptions from a consortium of pharmaceutical companies, and several private donors. In addition, a group of biotechnology companies contribute to AfCS research by supplying equipment and reagents essential to specialized, state-of-the-art techniques.
From page 244...
... But now instead of black shading, the area inside the cell contained a bewildering array of insulin substrate proteins, second messengers, kinases, adaptors, glucose transporters, and transcription factors, connected by a labyrinth of intersecting lines and arrows. At the bottom the new caption reads, "Now we really understand insulin signaling." Do we?
From page 245...
... In the living organism, "signaling pathways interact with one another and the final biological response is shaped by the interaction between pathways." Like the fiber optic systems that route telephone calls or the hardware that shuttles data inside your computer, biological communication is the product of integrated circuits operating as a network, and the collective behavior of that network, not the sum total of the activity in myriad individual units, is what determines the cell's responses to external signals. "The term `pathway' implies a linear structure -- you flip a switch and a particular biological process happens at the other end.
From page 246...
... . can be used to plan experimental strategies," while "cycles of modeling and experimental validation gradually result in the convergence of the model's predictions with the measured parameters of the natural biological system." Finally, Werner argues, the quantitative rigor demanded by model building exposes fuzzy thinking; as he puts it, models "force a new perspective on the subject matter.
From page 247...
... Today, the overwhelming majority of drugs in the modern pharmacopoeia act by talking to cells in their own language. The discovery of new signals and new receptors, as well as the intracellular relays they engage, has offered new targets for pharmaceutical researchers, opportunities that are already beginning to yield more effective and less toxic medications -- and, at the same time, have revealed the pitfalls of concentrating on individual receptors or kinases instead of the larger picture, particularly the interrelationships between signaling pathways.
From page 248...
... The drug, Herceptin, is a monoclonal antibody to a domain in the protein encoded by the her2/neu gene, related to the receptor for epidermal growth factor. Malignant cells in some breast cancer patients contain extra copies of the her2/neu gene; these cells proliferate extravagantly because they're saturated with extra receptors as a consequence (as many as 1.5 million receptors per cell, compared to about 50,000 on normal cells)
From page 249...
... A third signaling oriented drug, AstraZenecas' Iressa, was approved in 2003 for the treatment of non-small-cell lung cancer. Like Herceptin, Iressa shuts off the relentless screaming of a corrupted epidermal growth factor signaling pathway, in this case due to mutations in the growth factor receptor itself.
From page 250...
... Medications that finally hurt cancer more than they hurt the patient, they are leading oncologists to suggest -- cautiously -- that drugs like Gleevec might turn cancer into a chronic but manageable disease. At the same time pharmaceutical researchers are making progress in the war on cancer with new drugs that target signaling proteins, they are running into roadblocks in more traditional areas of signaling research.
From page 251...
... "We are still at the stage of identifying the various partners that can be engaged by the receptor, and we are only just getting the first glimpses into their potential roles in controlling signaling selectivity and efficacy," he adds. "Undoubtedly, this will dramatically change the way we approach signaling selectivity, and will hopefully provide new insights into how we can modulate GPCR signaling in a selective manner." That's why pharmaceutical companies are joining government agencies and the private sector in bankrolling the AfCS -- they recognize that the more we know about the complexities of signaling, the more successful they will be at identifying and exploiting new therapeutic opportunities.
From page 252...
... And the look on that little kid's face is all that matters." Getting back to business, he assures the audience that "progress has been substantial, especially in the last couple of months." They'll be hearing details of the methods Alliance laboratories have developed for preparing and propagating each of the two cell types, he notes. And he explains that much of the data they'll see will come from so-called ligand screens intended to flesh out the "parts list" for the signaling pathways of each cell and "measure the spectrum and pattern of responses." Basically, the major goal of this part of the work, Gilman observes, "is to collect empirical information for use at later stages." For example, investigators want to know if all ligands that work through G protein­coupled receptors behave similarly or if they differ and, if so, how.
From page 253...
... Still, Myocyte Committee Chair Jim Stull is cautiously optimistic, reporting that his team can maintain the cells for at least 24 hours without death or degeneration. With a preparation that finally lives long enough to be tested, he says, they have a "green light to begin the single ligand screen for this cell type." At the end of the day, Henry Bourne sounds a note of caution.
From page 254...
... Dinner that evening is at the infamous Texas Book Depository -- on the seventh floor, not the sixth, where Lee Harvey Oswald took aim. Here, scientists collect in groups to discuss the days' presentations, people they have known only by teleconference until today.
From page 255...
... RNA interference does work in mammalian cells -- just not ours." Despite heroic efforts, investigators could not get the technique to work in the B lymphocyte. Worse, they could not get the technique to work in their back-up option, the WEHI-231 cell -- a disappointment Gilman calls the "ultimate ironic shaft." Reluctantly, the AfCS Steering Committee decided to give up
From page 256...
... Following Henry Bourne's suggestion, Alliance investigators limited more detailed studies of RAW264.7 signaling pathways to a single "X module" encompassing the responses of calcium and PIP3 to three ligands. In the first stage of this project, they compiled a parts list of about 200 signaling proteins.
From page 257...
... And in the end, we've generated a hypothesis machine, one that can and should inspire lots of questions." A SYSTEM OF CENTERS, THE PRINCIPLES OF POEMS Ever since the publication of A Pattern Language more than 30 years ago, Christopher Alexander has felt that his theory was not quite complete, that he was missing something vitally important. Now, he says, he knows what that something was -- the big picture.
From page 258...
... 258 THE LANGUAGE OF LIFE In his latest work, The Phenomenon of Order, the first of four books intended to constitute an "essay on the art of building and the nature of the universe," Alexander argues that beautiful buildings-and living things -- display "wholeness," a quality he attributes to entities he calls "centers." He defines a center as "a physical set that occupies a certain volume in space and has a special marked coherence" and emphasizes that centers not only create the wholeness but are created by it; they seem to emerge from it as intersecting elements of a larger pattern, rather than distinct units. In contrast to the way we are used to defining space -- the proverbial four walls-centers have fuzzy boundaries, are more fluid; they do not necessarily correspond to items we can name.
From page 259...
... As a result, "the fifteen properties appear as geometric features of the way that space is organized in nature." Deep interlock and ambiguity, for example, appear in the pattern of a giraffe's coat or the involutions of the brain. And not-separateness is an integral feature of any ecosystem, from a backyard garden to a rain forest, and "corresponds to the fact that there is no perfect isolation of any system" -- even a system as small as the collective signaling pathways in a single cell.
From page 260...
... The exchange of chemical messengers within these networks weaves a tapestry of larger patterns that link cell to cell, tissue to tissue. From these intricate and meaningful conversations between nerve and muscle, bone and blood, mesoderm and ectoderm, cell cycle and death machinery emerge bodies that are dense with meaning, organisms that are also poems.


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